The objective of these contracts is to maintain our capacity to test the efficacy of new anti-viral therapies in small, non-primate animal models; these contracts represent, in part, a recompetition of the small animal retrovirus models, with an expansion to include combinations of two drugs. Other initiatives will address non-human primate models. The present initiative will maintain our capacity to test efficacy of new therapies early in drug development. The variety of models available will allow the choice of model with the appropriate molecular targets, such as those that are specific to HIV. The addition of a SCIDS mouse model reconstituted with human tissue and infected with HIV will allow efficacy to be measured directly against HIV in vivo. The inclusion of combination therapies in this initiative is especially important to the work of the Developmental Therapeutics Branch. Many of the therapies now in use or proposed for use in the clinical treatment of HIV infection in humans are limited in use because of toxicity. In an attempt to circumvent these toxicities, regimens combining more than one therapeutic agent are being proposed for clinical use; already a large number of clinical trials are underway or proposed to study AZT in combination with other drugs. With the recent identification and isolation of drug-resistant strains of HIV, use of combined therapies is likely to increase. Thus, there is a need to investigate the efficacy of new therapies in animal models and to extend those studies to include combinations that are likely to occur in the clinic.